Preclinical Development of an AAV8-hUGT1A1 Vector for the Treatment of Crigler-Najjar Syndrome
| Autor: | Collaud, Fanny, Bortolussi, Giulia, Guianvarc'h, Laurence, Aronson, Sem, Bordet, Thierry, Veron, Philippe, Charles, Severine, Vidal, Patrice, Sola, Marcelo Simon, Rundwasser, Stephanie, Dufour, Delphine, Lacoste, Florence, Luc, Cyril, Wittenberghe, Laetitia, Martin, Samia, Le Bec, Christine, Bosma, Piter, Muro, Andres, Ronzitti, Giuseppe, Hebben, Matthias, Mingozzi, Federico, Guianvarc’h, Laurence |
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| Přispěvatelé: | Généthon, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), International Centre for Genetic Engineering and Biotechnology (ICGEB) (Trieste), University of Amsterdam [Amsterdam] (UvA), Association française contre les myopathies (AFM-Téléthon), CCSD, Accord Elsevier, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Tytgat Institute for Liver and Intestinal Research, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Gastroenterology and Hepatology, École Pratique des Hautes Études (EPHE), Généthon, Evry, Trophos S.A., École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), GENETHON 3, Centre Technique Industriel des Entreprises du Secteur des Corps Gras |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
liver gene transfer lcsh:QH426-470 [SDV.IMM] Life Sciences [q-bio]/Immunology Crigler–Najjar syndrome Transgene Genetic enhancement Biology Article 03 medical and health sciences 0302 clinical medicine Genetics medicine Potency Vector (molecular biology) lcsh:QH573-671 Molecular Biology Gene Crigler-Najjar syndrome lcsh:Cytology HEK 293 cells Transfection medicine.disease 3. Good health lcsh:Genetics AAV vector 030104 developmental biology [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology 030220 oncology & carcinogenesis [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology Cancer research Molecular Medicine [SDV.IMM]Life Sciences [q-bio]/Immunology UGT1A1 long-term safety |
| Zdroj: | Molecular Therapy-Methods and Clinical Development Molecular Therapy-Methods and Clinical Development, Nature Publishing Group, 2019, 12, pp.157-174. ⟨10.1016/j.omtm.2018.12.011⟩ Molecular Therapy-Methods & Clinical Development Molecular Therapy-Methods and Clinical Development, 2019, 12, pp.157-174. ⟨10.1016/j.omtm.2018.12.011⟩ Molecular Therapy. Methods & Clinical Development Molecular therapy. Methods & clinical development, 12, 157-174. Nature Publishing Group Molecular Therapy-Methods & Clinical Development, 2019, 12, pp.157-174. ⟨10.1016/j.omtm.2018.12.011⟩ Molecular Therapy: Methods & Clinical Development, Vol 12, Iss, Pp 157-174 (2019) |
| ISSN: | 2329-0501 |
| Popis: | Adeno-associated viruses (AAVs) are among the most efficient vectors for liver gene therapy. Results obtained in the first hemophilia clinical trials demonstrated the long-term efficacy of this approach in humans, showing efficient targeting of hepatocytes with both self-complementary (sc) and single-stranded (ss) AAV vectors. However, to support clinical development of AAV-based gene therapies, efficient and scalable production processes are needed. In an effort to translate to the clinic an approach of AAV-mediated liver gene transfer to treat Crigler-Najjar (CN) syndrome, we developed an (ss)AAV8 vector carrying the human UDP-glucuronosyltransferase family 1-member A1 (hUGT1A1) transgene under the control of a liver-specific promoter. We compared our construct with similar (sc)AAV8 vectors expressing hUGT1A1, showing comparable potency in vitro and in vivo. Conversely, (ss)AAV8-hUGT1A1 vectors showed superior yields and product homogeneity compared with their (sc) counterpart. We then focused our efforts in the scale-up of a manufacturing process of the clinical product (ss)AAV8-hUGT1A1 based on the triple transfection of HEK293 cells grown in suspension. Large-scale production of this vector had characteristics identical to those of small-scale vectors produced in adherent cells. Preclinical studies in animal models of the disease and a good laboratory practice (GLP) toxicology-biodistribution study were also conducted using large-scale preparations of vectors. These studies demonstrated long-term safety and efficacy of gene transfer with (ss)AAV8-hUGT1A1 in relevant animal models of the disease, thus supporting the clinical translation of this gene therapy approach for the treatment of CN syndrome. Keywords: AAV vector, Crigler-Najjar syndrome, UGT1A1, liver gene transfer, long-term safety |
| Databáze: | OpenAIRE |
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